Molecular mechanisms underlying wm and gm pathology during neuroinflammation
MS is now regarded as a global CNS disease. Previously thought to be a disease of the wm characterized by inflammatory demyelinating focal white matter lesions, it has become increasingly evident over the last two decades that primary gm damage is a significant component of MS pathophysiology. This type of damage is characterized by severe pathology occurring within the context of less significant inflammation and blood brain barrier (BBB) loss of function. Our investigations of multiple EAE variants have found that gm pathological features are reproduced in the model.
To elucidate the spatio-temporal and pathological relationships between white and grey matter mechanisms, we have developed a range of approaches. These include histology, quantitative confocal microscopy for neuronal, glial and stress markers and laser microdissection followed by expression profiling on disease/pathway-specific arrays. Analyses are performed on wm and adjacent gm regions, for example in the cervical spinal cord and cerebellum. When used over a time course, these approaches enable comparisons of disease evolution at the cellular and molecular levels.
Currently they are being used to evaluate:
(1) The kinetics of BBB breakdown and repair.
(2) The relationship between inflammation, demyelination, axonal/neuronal damage, glial responses and cellular stress in each CNS compartment.
(3) Characterization of the inflammatory environment generated in each compartment, and,
(4) The relationship between stress and neuronal apoptosis.
These combined approaches also allowed the development of a workflow for the evaluation of the efficacy of MS drugs on wm and gm independently.